The present invention relates to a novel process for preparing uracil and cytosine derivatives and novel chemical compounds so produced.
Uracil has been reacted with various compounds to achieve substitution in the 5 position, see "Chlorination of 2,4-Diketotetrahydropyrimidines by Action of a Mixture of Superoxol and Hydrochloric Acid", Jour. Am. Chem. Soc., Vol. 65, pt. 1, pp. 1218-1219 (1943); "Action of Alkali and Ammonia on 2,4-Dialkoxypyrimidines", Jour. Am. Chem. Soc., Vol. 56, pt. 1, pp. 134-139 (1934); "The Reaction of Bromine with Uracils", Jour. Org. Chem., Vol. 24, p. 11, January, 1959; Wang, "Reaction of Bromine with Uracils", Nature 180, pp. 91-92 (July 13, 1957), and Brown infra.
The reaction of bromine or chlorine with uracil is as follows: ##STR1##
Numerous references may be cited which demonstrate the extreme reactivity of fluorine in contrast to the other halogens. For example, see M. Hudlicky, "Chemistry of Organic Fluorine Compounds", The MacMillan Co., New York (1962), and J. H. Simons, "Fluorine Chemistry", Vol. 1, Academic Press, Inc., New York, New York (1950). This extreme reactivity and the presumed required intermediacy of a hypohalous acid addition to the double bond would preclude the predictability of the reaction product of the aqueous fluorination of uracil.
The reaction of elemental fluorine with organic compounds has been studied extensively since the discovery of the gas by Henri Moissan in 1886. Moissan found that unlike chlorine, bromine and iodine, the unmoderated reaction of fluorine with organic compounds results in ignition and ultimate decomposition of the organic compound to smaller molecules. This greatly increased reactivity of fluorine compared to the other halogens is readily explained by comparing the heats of reaction of the halogens as in the following reactions. See M. Hudlicky, "Chemistry of Organic Fluorine Compounds", p. 72, The MacMillan Co., New York (1962).
______________________________________ .DELTA.H.degree. (K cal/mole) X = F Cl Br I ______________________________________ C .dbd. C + X.sub.2 .fwdarw. CX--CX -107.2 -33.1 -18.8 + 1.2 C--H + X.sub.2 .fwdarw. C--X+HX -102.5 -22.9 - 6.2 +13.7 ______________________________________
Since the carbon-carbon bond energy is only about 60 K cal/mole, it is quite evident that unless the heat of reaction is removed rapidly the heat evolved in fluorination is more than sufficient to destroy the carbon skeleton.
A number of methods have been used in which the heat of reaction is dissipated rapidly enough to give fair yields of fluorinated product. The more common methods are: (1) bubbling a mixture of fluorine and an inert gas through a cold liquid; (2) conducting away the heat of reaction by conducting the reaction in the presence of metal packing; and (3) addition of very large amounts of an inert diluent gas. See M. Stacey, J. C. Tatlow, and A. G. Sharpe, "Advances in Fluorine Chem.", Vol. 2, pp. 196-208, Butterworth, Inc., Washington, D.C. (1961); M. Hudlicky, "Chemistry of Organic Fluorine Compounds", The MacMillan Co., New York (1962); and J. H. Simons, "Fluorine Chemistry", Vol. 1, Academic Press, Inc., New York, N.Y. (1950).
An aqueous medium has seldom been used to assist in fluorination of organic compounds. Reference may be made to the work of Banks, Haszeldine and Lalu, Chem. and Ind. (London), 1803 (1964), CA 62, 428 g. (1965), in which esters of carbamic acid were fluorinated. ##STR2##
Since uracil exists predominantly in the oxo or keto form, see D. J. Brown, "The Pyrimidines", p. 9, Intersciene Publishers, Inc., New York (1962), the results of Bank's work would lead one to believe that fluorination of uracil would result in N fluorination rather than C fluorination, i.e., would yield products containing N-F groups.
It is also known to prepare 5-fluorouracil by reacting uracil mixed with a diluent amount of acetic acid, anhydrous hydrofluoric acid or sulfuric acid and treating the mixture with fluorine mixed with nitrogen as an inert gas at a temperature of 20.degree. to 25.degree. C., see Belgian Pat. No. 748,468 to Knuniants et al. However, the yield of 5-fluorouracil produced by this process is generally low and the presence of certain diluents, such as acetic acid, in the reaction mixture tends to give rise to undesirable secondary reaction products.
As previously stated, the process of the present invention is useful for the fluorination of uracil to form 5-fluorouracil, as well as 5-fluorocytosine and novel uracil and cytosine derivatives. The use of 5-fluorouracil in the treatment of cancer, particularly dermatological cancers, is known and well documented. See Heidelberger et al, "Studies on Fluorinated Pyrimidines II--Effects on Transplanted Tumors", Cancer Research, Vol. 18, p. 305 (1958), and Heidelberger et al, "Fluorinated Pyrimidines, A New Class of Tumor-Inhibitory Compounds", Nature, Vol. 179, p. 663, Mar. 30, 1957. Bardos et al, Nature 183, 612 (1959), and Brown, D. J. "The Pyrimidines", p. 175, Interscience, New York (1962).
The commercially employed method for the synthesis of 5-fluorouracil disclosed in U.S. Pat. No. 2,802,005 utilizes extremely toxic monofluoro intermediates. See Stacy et al, "Advances in Fluorine Chemistry", Vol. 2, pp. 196-208, Butterworth, Washington, D.C. (1961). Large scale production has not been undertaken primarily because of the difficulty in handling these intermediates.
It is also known to prepare various uracil derivatives by reacting 5-fluorouracil with chlorine or bromine in the presence of water, as disclosed in Duschinsky et al U.S. Pat. No. 3,277,092. The reaction may be described by the following scheme: ##STR3##
This procedure requires a separate reduction step to remove the bromine, or chlorine, as the case may be, to produce the uracil derivative, in this case 5-fluoro-6-hydroxy-5,6-dihydrouracil.
The direct synthesis of 5-fluorocytosine by the reaction of cytosine with trifluoromethyl hypofluorite is disclosed by Robins et al, "A Direct Synthesis of 5-Fluorocytosine and Its Nucleosides Using Trifluoromethyl Hypofluorite", J.C.S. Chem. Comm. 19, 1972. A similar process is used to produce nucleosides of 5-fluorocytosine.
Uses for 5-fluorocytosine are disclosed in U.S. Pat. Nos. 3,368,938 and 2,945,038, the disclosures of which are hereby incorporated by reference.